Selenium is an element essential for metabolism, but in the wrong form and in inappropriate amounts it is cytotoxic. This may be advantageous in the context of carcinostatic properties. Spallholz, J. E., in a review article published in Free Radical Biology and Medicine (1994) 17:45-64, proposed that the toxic selenium species is the metabolic selenide RSe− anion. The anion can participate in transthiolation reactions and generate superoxide, hydrogen peroxide and perhaps other cascading oxyradicals, according to this proposal. In a later paper from the same group, Stewart, M. J., et al., Free Radical Biology and Medicine (1999) 26:42-48, it is reported that catalytic selenite, selenocystine and selenocystamine induced apoptosis and were cytotoxic in keratinocytes, but selenomethionine was not cytotoxic and did not induce cellular apoptosis at the concentrations studied. Selenomethionine has also been shown to act as a cancer chemoprotectant by Ip, et al., Cancer Res. (1990) 50:1206-1211; El-Bayoumy, K., et al., Cancer Res. (1992) 52:2402-2407. Selenium compounds shown to inhibit carcinogenesis in rodents have been reported by Yan, Y., et al., Biochem. Pharmocol. (1993) 45:429-437.
Apparently, diselenide forms of organic selenium compounds, such as selenocystine and selenocystamine can be converted to the toxic form RSe−. However, mammalian cells do not readily convert the monoselenide forms to toxic moieties. Thus, selenomethionine, selenohomocysteine and selenocysteine are relatively nontoxic and noncarcinostatic.
Selenodithiols have been used to inhibit proliferation of cancer cells as described in U.S. Pat. No. 5,104,852 and selenium compounds which would otherwise be toxic have been used therapeutically in small enough concentrations as described in U.S. Pat. No. 4,512,977.
It has now been found that a particularly effective protocol for treatment of tumors comprises using the nontoxic forms of selenium as pro-drugs when the targeted cells are provided with a means to convert the pro-drugs to the toxic forms. The pro-drugs themselves can be cytotoxic if at sufficiently high levels. Kajander, E. O., et al., Biochem J. (1990) 267:767-774. However, these levels are several orders of magnitude higher than those required for cytotoxicity of compounds that can readily generate RSe− in cells.